The long term objectives of the proposed work are to increase knowledge regarding the neurochemical events leading to the acute and chronic behavioral effects of ethanol. Past results indicate that low level hyperbaric exposure represents a direct antagonist of ethanol's initial molecular action(s) that can be used, in place of a more traditional, stereospecific, receptor antagonist, to investigate the cascade of events leading to acute intoxication, tolerance and physical dependence. The Specific Aims are: 1) To further characterize the mechanism(s) by which hyperbaric exposure antagonizes acute and chronic behavioral effects of ethanol. This work will determine the specificity of the antagonism with respect to the acute behavioral effects of other alcohols, general anesthetics and non-anesthetic drugs; will determine whether hyperbaric exposure represents a competitive antagonist of ethanol's acute activating and depressant effects on locomotor activity; will determine whether increased general excitability contributes to the antagonism; and will investigate the mechanism by which hyperbaric exposure antagonizes the development of chronic functional tolerance and dependence; 2) To use hyperbaric exposure as a tool for investigating the neurochemical changes which mediate the stimulant and depressant effects of ethanol. These studies will test hypotheses regarding the importance of dopaminergic and prostanoid systems in meidating intoxication; and 3) To use hyperbaric exposure as a tool for investigating whether ethanol-induced membrane changes underlie the development of chronic functional tolterance and physical dependence. These studies will test hypotheses suggesting that adaptive membrane changes mediate chronic behavioral effects of ethanol. To achieve these goals, the effects of exposure to 12 atmospheres absolute helium-oxygen on sensitivity to the behavioral and neurochemical effects of ethanol and other drugs will be determined. Behavioral studies will use locomotor activity, duration of righting reflex loss, wake-up ethanol concentrations, seizure threshold, intoxication and withdrawal ratings to assess sensitivity and response to acute and chronic ethanol administration. Brain synaptosomal plasma membrane composition and fluidity, catecholamine turnover and prostanoid levels will be used as neurochemical indices of the effects of ethanol and pressure. We hope that this work will help in the identification of specific targets at which therapeutically relevant antagonists can be directed to reduce alcohol-related problems.